To investigate the etiology of periodontal diseases, possible mechanisms of tissue destruction, and the effects of therapeutic measures, a series of clinical experiments have been designed in which the interrelationships between composition of the plaque microbiota, immunologic response and potential mediators of local tissue pathology are studied in a patient population with advanced destructive disease. Extensive clinical measurements will be carried out to verify that each patient is in an active state of disease at the time of investigation and to monitor the effectiveness of therapeutic regimens tested. Local levels of administered agent will be assessed by pharmacologic monitoring in order to verify that effective dosage has been achieved. Clinical disease activity will be correlated with parameters measured in the laboratory in order to seek possible laboratory aids to diagnosis. The patient's immunologic response to his or her own microbial populations will be tested. By determining which organisms are eliminated or suppressed by different therapeutic regimens and monitoring disease activity, it is hoped that specific pathogens responsible for active periodontal disease can be identified. These findings should lay the basis of preventive therapy directed toward elimination of specific pathogens. By determining the nature of the host response to resident organisms, it is hoped that a more precise definition of pathogenic mechanisms will be obtained which will direct efforts seeking alternative therapeutic measures. By determining the clinical effect of various forms of periodontal therapy, it is hoped that more rational approaches for treating periodontal disease will be devised. At this time, few definitive tests are known which can be used to guide therapy, or to assess its effect. By thoroughly investigating the multiplicity of interrelated facts which are associated with the periodontal disease process, it is hoped that bases for rational prevention and therapy will be established.